Gut and Liver https://doi.org/10.5009/gnl20330 pISSN 1976-2283 eISSN 2005-1212 Review Article

Treatment of Refractory Infection-Tailored or Empirical Therapy

Jyh-Ming Liou1,2,3, Yi-Chia Lee1,2,4, and Ming-Shiang Wu1,2, for the Taiwan Gastrointestinal Disease and Helicobacter Consortium 1Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, 2Department of Internal Medicine, National Taiwan University College of Medicine, 3Department of Medicine, National Taiwan University Cancer Center, and 4Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan

Article Info The treatment of refractory Helicobacter pylori remains challenging in clinical practice. Factors Received November 7, 2020 that should be considered in the treatment of refractory H. pylori infection include treatment Accepted December 14, 2020 length, dosage of antibiotics and proton pump inhibitors (PPIs), number of drugs, and the selec- tion of appropriate antibiotics. Extending the treatment length of triple therapy and non-bismuth Corresponding Author quadruple therapy to 14 days may increase the eradication rate compared with a shorter period Jyh-Ming Liou (7 or 10 days). The use of a higher dose of PPIs or vonoprazan may also increase the efficacy of ORCID https://orcid.org/0000-0002-7945-5408 triple therapy. Four-drug therapy, including bismuth or non-bismuth quadruple therapies, usually E-mail [email protected] achieve higher eradication rates than triple therapy. The addition of bismuth or metronidazole to levofloxacin-amoxicillin-PPI therapy may also increase the eradication rate. Therefore, four- Jyh-Ming Liou, Yi-Chia Lee, and Ming-Shiang drug therapies containing a higher dose of PPIs for 14 days are recommended in the third-line Wu contributed equally to this work as first treatment setting for refractory H. pylori infection. The selection of appropriate antibiotics may authors. be guided by susceptibility testing or empirically by history. Tailored therapy guided by susceptibility testing or genotypic resistance is recommended whenever possible. However, properly designed empirical therapy based on prior medication history (i.e., avoid the reuse of clarithromycin or levofloxacin empirically) is an acceptable alternative to tailored therapy after considering accessibility, cost, and the preference of the patient. (Gut Liver, Published online March 31, 2021)

Key Words: Helicobacter pylori; Refractory; Third-line; Eradication; Resistance

INTRODUCTION used second-line rescue regimens.1,5,7,8 Yet, about 10% to 20% of patients cannot be cured with either one of them. Eradication of Helicobacter pylori reduces the recur- Patients who experience treatment failure after two or rence rate of , cures two-thirds of pa- more eradication therapies are usually termed as those tients with mucosal-associated lymphoid tissue lymphoma, with refractory H. pylori infection.9,10 Overall, it is esti- and reduces the risk of gastric cancer.1-4 Clarithromycin mated that 3% to 10% of H. pylori-infected subjects would triple therapy is one of the most commonly used regimen require third-line rescue therapy for refractory H. pylori in the first-line treatment.1,5 However, the eradication rate infection. Yet, treatment of refractory H. pylori infection of clarithromycin triple therapy is now lower than 80% in remains a challenge in clinical practice and some patients the first-line treatment due to the global rising prevalence are left untreated. Therefore, we reviewed current evidence of clarithromycin resistance.6,7 Levofloxacin triple therapy and proposed strategies to optimize the treatment for re- and bismuth quadruple therapy are the most commonly fractory H. pylori infection.

Copyright © Gut and Liver. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

www.gutnliver.org Gut and Liver, Published online March 31, 2021

SHOULD WE RECOMMEND RESCUE H. pylori strains were already present in patients who THERAPY FOR ALL PATIENTS WITH failed after levofloxacin-based and clarithromycin-based REFRACTORY H. pylori INFECTION? triple therapy.15 A proportion of H. pylori bacteria attach to gastric mucosal cells and form a biofilm, and some are There are contradictory viewpoints about whether pa- intracellular, which means they are inaccessible to many tients with refractory H. pylori infection should be actively antibiotics.16 This biofilm phenomenon which has been treated with rescue therapy or they may be left untreated. demonstrated with H. pylori in vitro and is likely also pres- Some physicians considered that further rescue therapy is ent in vivo. H. pylori can also survive intracellularly mak- not mandatory because gastric cancer develops only in 1% ing them inaccessible to topical therapy and to drugs that to 3% of H. pylori-infected subjects and there are potential penetrate cells poorly.16 Acetylcystein was shown to destroy concerns about increased risk of antibiotic resistance at the biofilm and may increase the efficacy of eradication individual level as well as in the community.11,12 However, therapy for refractory H. pylori infection in some studies, most experts considered that physicians should recom- but the effect remains controversial.17 Most proton pump mend rescue therapy for these patients since eradication of inhibitors (PPIs) are metabolized through the CYP2C19 H. pylori reduces the risk of gastric cancer.2,3,4,7 Of course, pathway and the eradication rate is lower in patients with the patients can make their own decisions according to CYP2C19 extensive metabolizer.18 Increase the dosage of their preference judging from the benefit and risk of rescue PPIs may be required to provide adequate acid suppression therapy. For example, patients who carry the higher risk of and higher eradication rate in such circumstances.18,19 gastric cancer, such as the presence of premalignant lesions and positive family history are candidates for the rescue therapy. OPTIMIZATION OF THIRD-LINE TREATMENT

Optimization of the regimens is important to achieve FACTORS ATTRIBUTABLE TO the best cure rates used in the treatment of refractory H. TREATMENT FAILURE pylori infection. The proposed strategies to optimize the eradication rate are shown in Table 1. These include ex- Physicians should try to identify factors leading to treat- tending treatment length to 14 days, use of higher dosage ment failure for their patients with refractory H. pylori or more potent acid suppression agents, optimization of infection. Common reasons for treatment failure include dosage of antibiotics, use of bismuth or non-bismuth qua- poor compliance to prior treatment, the presence of an- druple therapy, and selection of appropriate antibiotics ac- tibiotic resistance, insufficient delivery of drugs into the cording to susceptibility testing or empirically according to gastric mucous layer, rapid metabolism of treatment drugs, detailed medication history.19-26 and insufficient treatment length.13 Poor compliance of The intragastric location of H. pylori complicates thera- therapy may result from adverse effects or the complexity py as it requires consideration of many variables as the in- of drug administration of prior regimens.13 If the patient’s fection is both outside the body, attached to cells, and even compliance is good, the presence of antibiotic resistance within gastric cells.27 Factors that should be considered to is the most common reason for treatment failure.13 The recommend an optimal regimen include optimum drugs, high bacterial load makes it likely that antibiotic-resistant formulations, routes of administration, doses, dosing inter- H. pylori strains will be present when antibiotic therapy is vals, relation to meals, adjuvants, and duration of therapy.27 begun. The average H. pylori-infected stomach contains Optimum is defined as the best or most effective therapy huge numbers of H. pylori such that if the spontaneous possible in a particular situation. In subjects adherent to rate of development of resistance was only 1 in 10 million treatment, regimens are usually expected to achieve cure and 109 (100 million) organisms were present, one would rates reliably equal to or greater than 95% for infectious expect that a resistant subpopulation of H. pylori would diseases.4,27,28 already be present and cause the therapy to fail.4 H. pylori can also rapidly acquire new genotypic resistance to many 1. Duration of therapy commonly used antimicrobials. Our study showed that Duration is based on overcoming the persister effect the prevalence of clarithromycin resistance was 61% and and takes into account that PPIs do not achieve full effec- 95% in patients who experienced treatment failures after tiveness until after 3 or 4 days of administration.4,27,28 Ex- one and two eradication therapies, respectively.14 Another tending the treatment length of triple therapy for 14 days study showed that the gyrase A and 23S rRNA mutant was superior to the same regimen given for 7 days or 10

2 www.gutnliver.org Liou JM, et al: Treatment of Refractory Helicobacter pylori Infection

Table 1. Optimization of Rescue Therapy for Refractory Helicobacter pylori Infection Strategy Recommendation

Duration of therapy 14 Days Dosage of drugs PPIs Higher dosage PPIs ( 40 mg or equivalent twice daily) or vonoprazan 20 mg twice daily Amoxicillin 2,000–3,000 mg per day in 2–4 divided doses Levofloxacin 500 mg per day or 250 mg twice daily Sitafloxacin 100 mg twice daily Metronidazole 1,500–1,600 mg per day in 3–4 divided doses Tetracycline 1,500–2,000 mg per day in 3–4 divided doses Rifabutin 300 mg per day in 2 divided doses Clarithromycin 800–1,000 mg per day in 2 divided doses Number of drugs We recommended 4-drug therapy (bismuth or non-bismuth quadruple therapy) for refractory H. pylori infection How to choose antibiotics Guided by susceptibility testing or genotypic resistance whenever possible Empirical therapy to avoid reuse of clarithromycin and levofloxacin may be an acceptable alternative considering availability, cost, and preference of patient PPIs, proton pump inhibitors. days in the first-line treatment.22 Thus, various guidelines vonoprazan-based sitafloxacin triple therapy was superior have recommended duration of 14 days in the first-line to PPIs-based sitafloxacin triple therapy in the third-line treatment unless a shorter duration is locally proven to be treatment of H. pylori infection.31 non-inferior and produce a reliably high success rate.1,5,8,29 In the second-line or third-line treatment, the cure rates 3. Optimal dosage of antibiotics in rescue therapy of levofloxacin triple therapy were 58.3%, 68.2%, and Earlier studies showed that the use of higher dosage of 93.3% when the treatment length were 7, 10, and 14 days, metronidazole (up to 1,600 to 2,000 mg per day) may part- respectively.30 However, it is noteworthy that the benefit ly overcome the metronidazole resistance.13 Recent studies of extending the treatment length to 14 days is minimal also showed that the use of higher dosage of amoxicillin (up in susceptible strains.29 However, the eradication rate can to 750 mg three times or four times a day) may increase be increased in strains with clarithromycin resistance, the efficacy of dual therapy.32 The recommended dosage which is attributable to the effect for PPIs-amoxicillin dual of tetracycline is 500 mg four times a day in bismuth qua- therapy.18 Taken together, we recommend 14-day therapy druple therapy.1,5,8 In contrast, increase in clarithromycin for refractory H. pylori infection, but further well designed or levofloxacin dosage cannot overcome the resistance to trials are needed. these two antibiotics, respectively.

2. Dosage of PPIs 4. Number of drugs PPIs vary greatly in relative potency such that it is Several randomized trials showed that four-drug regi- impossible to compare regimens using different PPIs mens, including bismuth quadruple therapy and non- unless these differences are taken into account. For H. bismuth quadruple therapies (concomitant therapy, se- pylori eradication, 20 mg omeprazole equivalents, twice quential therapy, hybrid therapy) were more effective than daily is regarded as low dose PPI and 40 mg omeprazole triple therapy in the first-line treatment when given for the equivalents, twice daily regarded as high or double dose.19 same duration.20,21,23,26 Concomitant or sequential therapy Randomized trials showed that the use of higher dos- for 14 days, but not 10 days, was superior to 14-day triple age of PPIs may increase the efficacy of triple therapy.24 therapy in the first-line treatment.23,33 Triple therapy con- Therefore, it has been recommended to give double dose taining , amoxicillin and metronidazole for 2 PPIs because of the benefits obtained by increasing the weeks was suboptimal in the third-line therapy after failure anti-secretory effect with dual PPIs amoxicillin therapy. from clarithromycin-based therapy and fluoroquinolone- More recently, vonoprazan, a potassium-competitive acid based therapy.34 The eradication rates were 64% and 37% blocker, is shown to be more potent than PPIs, especially in in metronidazole-naive and metronidazole experienced those with CYP2C19 extensive metabolizer. Vonoprazan- patients, respectively.34 Systematic review and meta-anal- based triple therapy for 7 days was shown to be superior ysis showed that the efficacy of levofloxacin triple therapy to -based triple therapy for 7 days in Japanese, was lower than 80% in the second-line treatment.35 Hsu et especially in those infected with clarithromycin-resistant al.36 showed that addition of bismuth to levofloxacin triple strains.25 A recent randomized trial further showed that therapy cured 84% of patients (31/37) in the third-line

https://doi.org/10.5009/gnl20330 3 Gut and Liver, Published online March 31, 2021 63 (24/38) 62 (24/39) 91 (85/93) 83 (109/132) 78 (156/199) 97 (186/192) 77 (30/39) 94 (291/310) 90 (212/236) 86 (42/49) PP analysis 60 (24/40) 60 (25/42) 90 (85/94) 81 (109/135) 78 (160/205) 95 (189/200) 61 (30/49) 94 (291/310) 83 (211/254) 86 (42/49) ITT analysis 40 42 94 49 49 135 205 200 310 254 cases No. of

7 7 7 14 14 14 14 10 day 8–14 10–12 Duration, Duration, Rules to choose regimen to Rules ceptible drug or PPIs, doxycycline, and and doxycycline, PPIs, or drug ceptible rifampicin amoxicillin or triple PPIs, amoxicillin and and PPIs, amoxicillin or triple amoxicillin or clarithromycin levofloxacin - or clarithro levofloxacin metronidazole, or tetracycline mycin - or clarithro levofloxacin metronidazole, or tetracycline mycin - levo or metronidazole, or clarithromycin floxacin and PPI, bismuth, amoxicillin, infections: metronidazole and rifabutin; PPIs, bismuth, furazolidone, PPIs, bismuth, furazolidone, and rifabutin; PPIs, bismuth, or rifabutin; amoxicillin or amoxicillin furazolidone tetracycline, fabutin Quadruple: PPIs, bismuth, plus 2 antibiotics Quadruple: - sus amoxicillin, PPIs, with therapy Triple Quadruple: PPIs, bismuth, plus 2 antibiotics Quadruple: and doxycycline bismuth, PPIs, Quadruple: amoxicillin, PPIs, quadruple: Non-bismuth PPI, amoxicillin, Non-bismuth quadruple: plus with PPI, amoxicillin therapy Triple multidrug-resistant for Bismuth quadruple Triple therapy or quadruple therapy therapy or quadruple therapy Triple ciprofloxacin, PPIs, amoxicillin, Quadruple: or ri - levofloxacin PPI, amoxicillin, Triple: Infection 51/-/43 56/-/56 59/-/47 94/6/68 86/52/67 87/47/58 90/61/66 92/44/73 95/31/100 94/93.5/81 CLA/LEV/MET resistance rate, % rate, resistance

Helicobacter pylori Helicobacter 97.6 97.8 100 Culture Culture 95 (128/135)/ 74 (100/135) 80 (39/49) 96 (94/98) 93 (236/254) success rate success 100 (49/49) 95.8 (206/215) 98.7 (306/310)

PCR Agar E-test E-test E-test E-test E-test E-test E-test dilution PCR and Test used Test agar dilution 2 2 2 2 1 or 2 1 or 2 1 or 2 No. of Tx 2 or more 2 or more 1 or more

NC NC NC NC NC NC NC NC NC RCT Study design 40 38 39 43 45 41 (2004) 44 46 (2000) 42 47 (2002) et al. (2013) (2017) et al. (2006) (2013) (2018) (2012)

et al. (2019) et al. Author (year) et al. et al.

et al. et al.

et al. et al. Gasbarrini Cammarota Cammarota Liou Yahav Yahav Costa Yu Vicente Vicente Fiorini Liou Tay Tay Susceptibility Testing-Guided Therapy in Third-Line Treatment for for Treatment in Third-Line Therapy Testing-Guided 2. Susceptibility Table Data are presented percent (number/number). percent presented are Data controlled randomized RCT, study; NC, noncontrolled PP, per protocol; ITT, intention-to-treat; MET, metronidazole; LEV, levofloxacin; CLA, clarithromycin; therapy; number of prior eradication No. of Tx, pump inhibitors. PPIs, proton chain reaction; trial; PCR, polymerase

4 www.gutnliver.org Liou JM, et al: Treatment of Refractory Helicobacter pylori Infection treatment of H. pylori infection. The addition of bismuth However, there is limited evidence to show the superi- to rifabutin triple therapy (96.6%, 28/29) was shown to in- ority of tailored therapy over empirical therapy in rescue crease the eradication rate of rifabutin-based triple therapy therapies. In the first-line therapy, susceptibility testing- (66.7%, 18/27) in the third-line treatment.37 Taken togeth- guided therapy was more effective than empirical triple er, it is suggested to provide four-drug regimens (bismuth therapy for 7 or 10 days in the first-line treatment in a me- or non-bismuth quadruple therapy) as third-line or fourth- ta-analysis of randomized trials.48 Yet, two randomized tri- line salvage therapy. als showed that empirical bismuth quadruple therapy and empirical non-bismuth quadruple therapy were not infe- 5. How to choose antibiotics in third-line or fourth- rior to tailored therapy in China and Korea where the clar- line rescue therapies? ithromycin-resistant rate was higher than 15% to 20%.49,50 1) Susceptibility guided therapy Moreover, tailored therapy was not superior to empirical Ideally, therapy should be tailored by susceptibility test- therapy in three trials that recruited patients failed after one ing whenever possible. Tailored therapy is recommended eradication therapy.48 Of the only one randomized trial that by international consensus reports for patients with refrac- compared the efficacy of tailored therapy versus empirical tory H. pylori infection although the evidence level is low therapy for patients who failed after at least two eradication for such recommendation.1,4 The efficacy of susceptibility therapies, Liou et al.46 showed that the eradication rate of testing-guided therapy for refractory H. pylori infec- genotypic resistance guided therapy and empirical therapy tion has been reported in nine studies, as shown in Table were 78% and 72%, respectively. Therefore, our suggestion 2.38-47 Eight of them are noncontrolled case series, one is is that susceptibility testing or genotypic resistance should non-randomized controlled study, and another one is a be determined for patients with refractory H. pylori infec- randomized control trial. E-test was the most commonly tion whenever possible. However, properly chosen empiri- used method to detect antibiotic resistance (Table 2). The cal therapy according to the detailed medication history successful rate of culture ranged from 74% to 98%. The may be an as effective alternative considering accessibility resistance rate to clarithromycin, metronidazole, and levo- to susceptibility testing, patient preference, and cost. floxacin ranged from 51%–95%, 43%–100%, and 6%–52%, respectively. Bismuth quadruple therapy including a PPI, 2) Empirical therapy bismuth and another two susceptible antibiotics or non- Since the resistance rates are high in patients who fail bismuth quadruple therapy including a PPI plus another after regimens containing clarithromycin and levofloxacin, three antibiotics were the most commonly used regimens. these two antibiotics should not be reused empirically.1,8,51 The treatment length varied from 7 to 14 days. The overall The strategy to choose antibiotics for third-line and fourth- eradication rate of susceptibility testing-guided therapy line therapy is shown in Fig. 1.1,8,51 For patients who have ranged from 60% to 90% (Table 2). received regimens containing clarithromycin and levoflox-

Low or intermediate clarithromycin High clarithromycin resistance (<20%) resistance (>20%)

1st line Clarithromycin-based regimen Bismuth quadruple Sequential or concomitant (if bismuth not available)

Levofloxacin-based Bismuth quadruple Levofloxacin-based regimen 2nd line regimen Fig. 1. How to choose antibiotics Empirical empirically in rescue therapies. Avoid the reuse of clarithromycin or levofloxacin empirically in third-line Levofloxacin-based Bismuth quadruple Rifabutin-based regimen 3rd line regimen rescue treatment. "?" indicates that although sus- ceptibility testing guided therapy is ? recommended for patients who fail after a rifabutin-based regimen, 4th line Rifabutin-based regimen Susceptibility guided therapy there is limited evidence to support this recommendation.

https://doi.org/10.5009/gnl20330 5 Gut and Liver, Published online March 31, 2021 PP analysis 72.1 (49/68) 66.7 (128/192) 43.7 (28/64) 58.3 (7/12) 68.2 (15/22) 93.3 (14/15) 45.8 (11/24) 68.4 (80/117) 84.4 (82/97) 80.6 (25/31) 64.0 (16/25) 68.8 (22/32) 83.8 (31/37) - - - Eradication rate, % (No./No.) rate, Eradication ITT analysis 70.4 (49/70) 65.5 (131/200) 43.3 (28/65) 58.3 (7/12) 62.5 (15/24) 73.7 (14/19) 45.8 (11/24) 67.2 (80/119) 80.2 (81/102) 83.8 (31/37) 7 7 7 7 10 14 10 10 10 10 14 10 7–14 Duration, day Duration, Dosing frequency (three-in-one capsules containing metronidazole 125 mg, metronidazole potassium (three-in-one containing capsules ® (from 250 mg t.i.d. to 500 mg q.i.d.) and metronidazole (from 250 mg t.i.d. to 500 mg q.i.d.) 250 mg t.i.d. to (from 500 mg q.i.d.) and metronidazole 250 mg t.i.d. to (from 500 mg for the remaining 5 days (all b.i.d.). the remaining 500 mg for 140 mg, and tetracycline 125 mg) 3 tablets q.i.d. and a PPI b.i.d. 125 mg) 3 tablets 140 mg, and tetracycline levofloxacin (500 mg o.d.) levofloxacin Lansoprazole 30 mg b.i.d., amoxicillin 750 mg b.i.d., sitafloxacin 100 mg b.i.d. 750 mg b.i.d., sitafloxacin 30 mg b.i.d., amoxicillin Lansoprazole PPI (standard dose b.i.d.), bismuth subcitrate (120 mg q.i.d. or 240 mg b.i.d.), tetracycline (120 mg q.i.d. or 240 b.i.d.), tetracycline dose b.i.d.), bismuth subcitrate PPI (standard Pylera PPI standard dose b.i.d., levofloxacin 500 mg q.d., amoxicillin 1 g b.i.d. 500 mg q.d., amoxicillin dose b.i.d., levofloxacin PPI standard 500 mg q.d. 750 mg b.i.d., levofloxacin 10 mg b.i.d., amoxicillin 300 mg b.i.d. 750 mg b.i.d., levofloxacin 30 mg b.i.d., amoxicillin Lansoprazole 500 mg and tetracycline by PPI, levofloxacin 5 days, followed the first 1 g for PPI plus amoxicillin Levofloxacin-based therapy Levofloxacin-based Rabeprazole (20 mg b.i.d.), bismuth subcitrate (300 mg q.i.d.), amoxicillin (500 mg q.i.d.) and (300 mg q.i.d.), amoxicillin (20 mg b.i.d.), bismuth subcitrate Rabeprazole

NC NC RCT RCT Design Prospective Prospective Prospective Prospective Retrospective Retrospective (observational) (observational) 53 57 54 58 30 36 56 (2013) 55 (2014) (2014)

et al. (2012) (2016) (2011) (2017) et al.

et al. (2017) Author (year)

et al. et al. et al. et al.

et al. Tursi Tursi Rodríguez de Santiago Gisbert Lim Murakami Hsu Okimoto Okimoto Noh Bismuth quadruple therapy Bismuth quadruple Levofloxacin-based therapy Levofloxacin-based ITT, intention-to-treat; PP, per protocol; NC, noncontrolled study; RCT, randomized controlled trial; PPI, proton pump inhibitor; q.d., once a day; b.i.d., twice a day; q.i.d., four times a day. a day; q.i.d., four a day; b.i.d., twice q.d., once pump inhibitor; trial; PPI, proton controlled randomized RCT, study; NC, noncontrolled PP, per protocol; ITT, intention-to-treat; Bismuth Quadruple Therapy and Levofloxacin-Based Therapy in the Third-Line Treatment Setting Treatment in the Third-Line Therapy and Levofloxacin-Based Therapy 3. Bismuth Quadruple Table

6 www.gutnliver.org Liou JM, et al: Treatment of Refractory Helicobacter pylori Infection acin in their prior therapies, bismuth quadruple therapy is who harbor gyrase A mutations.53 However, there is limited recommended. For those who have not been treated with evidence to support the use of sitafloxacin-based therapy levofloxacin-containing regimen in their prior treatment, for treatment after failure from levofloxacin-based therapy. levofloxacin triple therapy, bismuth enhanced levofloxacin There are limited data on the efficacy of empirical bis- triple therapy, or non-bismuth quadruple therapy contain- muth quadruple therapy and levofloxacin-based therapy ing levofloxacin may be used. For those who have received in the third-line treatment of refractory H. pylori infec- bismuth quadruple therapy and regimens clarithromycin tion (Table 3).30,36,52-57 The reported efficacy of 7- to 14- and levofloxacin in their prior treatments, rifabutin-based day bismuth quadruple therapy containing PPIs, bismuth, triple or quadruple therapy may be used as rescue therapy. tetracycline, and metronidazole varied from 65% to 80% Whether re-treatment with bismuth quadruple therapy is in the third-line treatment.54,55 The efficacy of 7- to 14-day an option remains controversial, although a retrospective levofloxacin triple therapy or bismuth enhanced levofloxa- study in Korea showed that re-treatment with bismuth qua- cin triple therapy ranged from 43.3% to 84% in the third- druple therapy cured 75% of patients who failed after the line treatment (Table 3).30,36,53,56,57 The reported efficacy of same regimen in the second-line treatment.52 Sitafloxacin- sitafloxacin-based triple therapy varied from 54% to 93% based triple therapy was shown to be effective in patients in the third-line treatment (Table 4).53,58-66 Meta-analysis of

Table 4. Sitafloxacin Triple Therapy in the Third-Line Treatment Setting

Duration, Eradication rate, % (No./No.) Author (year) Dosing frequency day Overall Gyrase A wild Gyrase A mutant

Mori et al. (2019)59 Esomeprazole (20 mg, b.i.d.), amoxicillin (500 mg, q.i.d.), 10 81.6 (31/38) 94.7 (18/19) 68.4 (13/19) and sitafloxacin (100 mg, b.i.d.) Saito et al. (2019)60 Esomeprazole (20 mg, b.i.d.), amoxicillin (750 mg, b.i.d.), 7 54.2 (13/24) 66.7 (12/18) 20.0 (1/5) and sitafloxacin (100 mg, b.i.d.) Vonoprazan (20 mg, b.i.d.), amoxicillin (750 mg, b.i.d.), 7 93.0 (53/57) 96.4 (27/28) 91.7 (11/12) and sitafloxacin (100 mg, b.i.d.) Sue et al. (2019)31 Vonoprazan 20 mg b.i.d., amoxicillin 750 mg b.i.d., and 7 75.8 (25/33) - - sitafloxacin 100 mg b.i.d. Esomeprazole 20 mg b.i.d., rabeprazole 10 mg b.i.d., or 7 53.3 (16/30) - - lansoprazole 30 mg b.i.d.; amoxicillin 750 mg b.i.d.; and sitafloxacin 100 mg b.i.d. Hirata et al. (2016)61 Esomeprazole 20 mg b.i.d., amoxicillin 750 mg b.i.d., 7 83.3 (25/30) - - and sitafloxacin 100 mg b.i.d. Mori et al. (2016)62 Esomeprazole (20 mg, b.i.d.), amoxicillin (500 mg, q.i.d.), 10 81.0 (51/63) 100 (24/24) 70.3 (26/37) and sitafloxacin (100 mg, b.i.d.) Esomeprazole (20 mg, b.i.d.), metronidazole (250 mg, 10 72.4 (42/58) 100 (16/16) 66.7 (26/39) b.i.d.), and sitafloxacin (100 mg, b.i.d.) Sugimoto et al. (2015)63 PPI, amoxicillin 750 mg b.i.d. and clarithromycin 200 or 7 88.3 (83/94) - - 400 mg b.i.d. Furuta et al. (2014)64 Rabeprazole 10 mg b.i.d./q.i.d., amoxicillin 500 mg q.i.d., 7 84.1 (37/44) - - and sitafloxacin 100 mg b.i.d. Rabeprazole 10 mg b.i.d./q.i.d., amoxicillin 500 mg q.i.d., 14 88.9 (40/45) - - and sitafloxacin 100 mg b.i.d. Rabeprazole 10 mg b.i.d./q.i.d., metronidazole 250 mg 7 90.9 (40/44) - - b.i.d., and sitafloxacin 100 mg b.i.d. Rabeprazole 10 mg b.i.d./q.i.d., metronidazole 250 mg 14 87.2 (41/47) - - b.i.d., and sitafloxacin 100 mg b.i.d. Murakami et al. (2013)53 LPZ 30 mg b.i.d. + amoxicillin 750 mg b.i.d. + sitafloxacin 7 70.0 (49/70) 72.0 (28/39) 50.0 (1/2) 100 mg b.i.d. Matsuzaki et al. (2012)65 Rabeprazole (10 mg, q.i.d.), amoxicillin (500 mg, q.i.d.), 7 78.2 (61/78) 93.5 (29/31) 68.1 (32/47) and sitafloxacin (100 mg, b.i.d.) Hirata et al. (2012)66 Rabeprazole 10 mg b.i.d., amoxicillin 750 mg b.i.d., and 7 75.0 (21/28) 100 (1/1) 66.7 (2/3) sitafloxacin 100 mg b.i.d. Meta-analysis 80.2 (74.6–84.9)* b.i.d., twice a day; q.i.d., four times a day; PPI, proton pump inhibitor. *95% confidence interval.

https://doi.org/10.5009/gnl20330 7 Gut and Liver, Published online March 31, 2021 these studies revealed that the eradication rate of sitafloxa- are warranted to identify the best strategy in the treatment cin-based triple therapy was 80% (74.6% to 84.9%) (Table of refractory H. pylori infection. 4). The presence of gyrase A mutation was associated with increased risk of treatment failure (risk ratio, 1.3; 95% con- fidence interval, 1.2 to 1.4; p<0.001). The eradication rate CONFLICTS OF INTEREST appeared to be higher when more potent acid secretion inhibitor was used. A randomized trial showed higher ef- No potential conflict of interest relevant to this article ficacy of sitafloxacin-based triple therapy than that of levo- was reported. floxacin-based triple therapy.53 Therefore, sitafloxacin may be preferable to levofloxacin in the treatment of refractory H. pylori infection if it is available. ACKNOWLEDGEMENTS

The authors received grants from the Ministry of Sci- RIFABUTIN-BASED THERAPY IN ence and Technology (grant number: TCTC 109-2321-B- THE FOURTH-LINE TREATMENT OF 002-035 and MOST 108-2314-B-002-187, 109-2314-B- H. pylori INFECTION 002-090-MY3, 109-2314-B-002-202), the Ministry of Health and Welfare (grant number: MOHW109-TDU- There are limited data regarding the efficacy of rifab- B-211-114002, MOHW109-CDC-C-114-122118), “Center utin-based therapy in the fourth-line treatment. In a pro- of Precision Medicine” from The Featured Areas Research spective noncontrolled trial, Gisbert et al.67 showed that Center Program within the framework of the Higher Edu- rifabutin-based triple therapy containing rifabutin, amoxi- cation Sprout Project by the Ministry of Education (MOE) cillin and PPIs (standard dose twice daily) for 10 days was (grant number: NTU-109L901401), National Taiwan Uni- 50% (50/100). In another study, Mori et al.68 showed that versity Hospital (grant number: NTUH 109–P05), and the the efficacy of rifabutin-based triple therapy containing Liver Disease Prevention & Treatment Research Founda- esomeprazole (20 mg, four times a day), amoxicillin (500 tion, Taiwan. The funding source had no role in study de- mg four times a day), and rifabutin (300 mg, once daily) in sign, data collection, analysis or interpretation, report writ- the third-line or fourth-line treatment were 83.3% (10/12) ing or the decision to submit this paper for publication. for the 10-day group and 94.1% (16/17) for the 14-day The authors would like to express their special thanks group. Therefore, rifabutin-based therapy may be used as to the staff of the Eighth Core Lab, Department of Medical the fourth-line rescue treatment empirically for patients Research, National Taiwan University Hospital and mem- who have received clarithromycin-based therapy, levo- bers of Taiwan Gastrointestinal Diseases and Helicobacter floxacin-based therapy, and bismuth quadruple therapy in Consortium for their technological support. their prior treatments (Fig. 1).37,67,68

ORCID CONCLUSION Jyh-Ming Liou https://orcid.org/0000-0002-7945-5408 In conclusion, four-drug therapies containing higher Yi-Chia Lee https://orcid.org/0000-0002-8160-1216 dosage of PPIs for 14 days are recommended in the third- Ming-Shiang Wu https://orcid.org/0000-0002-1940-6428 line treatment of refractory H. pylori infection. Susceptibil- ity testing or genotypic resistance guided therapy is recom- mended whenever possible. However, properly designed REFERENCES empirical therapy, based on prior medication history (i.e., avoid reuse of clarithromycin or levofloxacin empiri- 1. Malfertheiner P, Megraud F, O'Morain CA, et al. Manage- cally), is an acceptable alternative to susceptibility testing- ment of Helicobacter pylori infection: the Maastricht V/ guided therapy after consideration of accessibility, cost, Florence Consensus Report. Gut 2017;66:6-30. and preference of patient. Rifabutin-based therapy may be 2. Lee YC, Chiang TH, Chou CK, et al. Association between used as the fourth-line rescue therapy for those who have Helicobacter pylori eradication and gastric cancer incidence: previously been treated with clarithromycin-based therapy, a systematic review and meta-analysis. Gastroenterology levofloxacin or sitafloxacin-based therapy, and bismuth 2016;150:1113-1124. quadruple therapy. Further large scale, randomized trials 3. Liou JM, Lee YC, El-Omar EM, Wu MS. Efficacy and long-

8 www.gutnliver.org Liou JM, et al: Treatment of Refractory Helicobacter pylori Infection

term safety of H. pylori eradication for gastric cancer pre- 17. Fontes LES, Martimbianco ALC, Zanin C, Riera R. N- vention. Cancers (Basel) 2019;11:593. acetylcysteine as an adjuvant therapy for Helicobacter pylori 4. Liou JM, Malfertheiner P, Lee YC, et al. Screening and eradi- eradication. Cochrane Database Syst Rev 2019;2:CD012357. cation of Helicobacter pylori for gastric cancer prevention: 18. Graham DY. Hp-normogram (normo-graham) for assessing the Taipei global consensus. Gut 2020;69:2093-2112. the outcome of H. pylori therapy: effect of resistance, dura- 5. Graham DY. Helicobacter pylori update: gastric cancer, tion, and CYP2C19 genotype. Helicobacter 2016;21:85-90. reliable therapy, and possible benefits. Gastroenterology 19. Graham DY, Lu H, Dore MP. Relative potency of proton- 2015;148:719-731. pump inhibitors, Helicobacter pylori therapy cure rates, and 6. Kuo YT, Liou JM, El-Omar EM, et al. Primary antibiotic meaning of double-dose PPI. Helicobacter 2019;24:e12554. resistance in Helicobacter pylori in the Asia-Pacific region: 20. Liou JM, Chen CC, Chen MJ, et al. Sequential versus triple a systematic review and meta-analysis. Lancet Gastroenterol therapy for the first-line treatment of Helicobacter py- Hepatol 2017;2:707-715. lori: a multicentre, open-label, randomised trial. Lancet 7. Liou JM, Lin JT, Chang CY, et al. Levofloxacin-based and 2013;381:205-213. clarithromycin-based triple therapies as first-line and 21. Liou JM, Chen CC, Chang CY, et al. Sequential therapy for second-line treatments for Helicobacter pylori infection: a 10 days versus triple therapy for 14 days in the eradication of randomised comparative trial with crossover design. Gut Helicobacter pylori in the community and hospital popula- 2010;59:572-578. tions: a randomised trial. Gut 2016;65:1784-1792. 8. Fallone CA, Chiba N, van Zanten SV, et al. The Toronto 22. Yuan Y, Ford AC, Khan KJ, et al. Optimum duration of regi- Consensus for the treatment of Helicobacter pylori infection mens for Helicobacter pylori eradication. Cochrane Data- in adults. Gastroenterology 2016;151:51-69. base Syst Rev 2013;(12):CD008337. 9. Liou JM, Bair MJ, Chen CC, et al. Levofloxacin sequential 23. Liou JM, Fang YJ, Chen CC, et al. Concomitant, bismuth therapy vs levofloxacin triple therapy in the second-line quadruple, and 14-day triple therapy in the first-line treat- treatment of Helicobacter pylori: a randomized trial. Am J ment of Helicobacter pylori: a multicentre, open-label, ran- Gastroenterol 2016;111:381-387. domised trial. Lancet 2016;388:2355-2365. 10. Liou JM, Chen CC, Chen MJ, et al. Empirical modified 24. McNicholl AG, Linares PM, Nyssen OP, Calvet X, Gisbert sequential therapy containing levofloxacin and high-dose JP. Meta-analysis: esomeprazole or rabeprazole vs. first- esomeprazole in second-line therapy for Helicobacter pylori generation pump inhibitors in the treatment of Helicobacter infection: a multicentre clinical trial. J Antimicrob Che- pylori infection. Aliment Pharmacol Ther 2012;36:414-425. mother 2011;66:1847-1852. 25. Murakami K, Sakurai Y, Shiino M, Funao N, Nishimura A, 11. Blaser MJ. Antibiotic use and its consequences for the nor- Asaka M. Vonoprazan, a novel potassium-competitive acid mal microbiome. Science 2016;352:544-545. blocker, as a component of first-line and second-line triple 12. Liou JM, Chen CC, Chang CM, et al. Long-term changes therapy for Helicobacter pylori eradication: a phase III, ran- of gut microbiota, antibiotic resistance, and metabolic domised, double-blind study. Gut 2016;65:1439-1446. parameters after Helicobacter pylori eradication: a mul- 26. Liou JM, Chen CC, Fang YJ, et al. 14 day sequential therapy ticentre, open-label, randomised trial. Lancet Infect Dis versus 10 day bismuth quadruple therapy containing high- 2019;19:1109-1120. dose esomeprazole in the first-line and second-line treat- 13. Vakil N, Megraud F. Eradication therapy for Helicobacter ment of Helicobacter pylori: a multicentre, non-inferiority, pylori. Gastroenterology 2007;133:985-1001. randomized trial. J Antimicrob Chemother 2018;73:2510- 14. Liou JM, Chang CY, Chen MJ, et al. The primary resistance 2518. of Helicobacter pylori in Taiwan after the national policy to 27. Graham DY. Antibiotic resistance in Helicobacter pylori: restrict antibiotic consumption and its relation to virulence implications for therapy. Gastroenterology 1998;115:1272- factors: a nationwide study. PLoS One 2015;10:e0124199. 1277. 15. Liou JM, Chang CY, Sheng WH, et al. Genotypic resistance 28. Graham DY, Tansel A. Interchangeable use of proton pump in Helicobacter pylori strains correlates with susceptibility inhibitors based on relative potency. Clin Gastroenterol test and treatment outcomes after levofloxacin- and clar- Hepatol 2018;16:800-808. ithromycin-based therapies. Antimicrob Agents Chemother 29. Liou JM, Chen PY, Kuo YT, Wu MS; Taiwan Gastrointestinal 2011;55:1123-1129. Disease and Helicobacter Consortium. Toward population 16. Cammarota G, Sanguinetti M, Gallo A, Posteraro B. Review specific and personalized treatment of Helicobacter pylori article: biofilm formation by Helicobacter pylori as a target infection. J Biomed Sci 2018;25:70. for eradication of resistant infection. Aliment Pharmacol 30. Noh HM, Hong SJ, Han JP, et al. Eradication rate by duration Ther 2012;36:222-230. of third-line rescue therapy with levofloxacin after Helico-

https://doi.org/10.5009/gnl20330 9 Gut and Liver, Published online March 31, 2021

bacter pylori treatment failure in clinical practice. Korean J ment for Helicobacter pylori infection. Clin Gastroenterol Gastroenterol 2016;68:260-264. Hepatol 2013;11:507-510. 31. Sue S, Shibata W, Sasaki T, et al. Randomized trial of vono- 44. Liou JM, Chen CC, Chang CY, et al. Efficacy of genotypic prazan-based versus proton-pump inhibitor-based third- resistance-guided sequential therapy in the third-line treat- line triple therapy with sitafloxacin for Helicobacter pylori. J ment of refractory Helicobacter pylori infection: a multicen- Gastroenterol Hepatol 2019;34:686-692. tre clinical trial. J Antimicrob Chemother 2013;68:450-456. 32. Yang JC, Lin CJ, Wang HL, et al. High-dose dual therapy 45. Costa S, Soares JB, Gonçalves R. Efficacy and tolerability of is superior to standard first-line or rescue therapy for He- culture-guided treatment for Helicobacter pylori infection. licobacter pylori infection. Clin Gastroenterol Hepatol Eur J Gastroenterol Hepatol 2017;29:1258-1263. 2015;13:895-905. 46. Liou JM, Chen PY, Luo JC, et al. Efficacies of genotypic 33. Chen MJ, Chen CC, Chen YN, et al. Systematic review with resistance-guided vs empirical therapy for refractory Heli- meta-analysis: concomitant therapy vs. triple therapy for the cobacter pylori infection. Gastroenterology 2018;155:1109- first-line treatment of Helicobacter pylori infection. Am J 1119. Gastroenterol 2018;113:1444-1457. 47. Yu L, Luo L, Long X, et al. Susceptibility-guided therapy for 34. Puig I, González-Santiago JM, Molina-Infante J, et al. Helicobacter pylori infection treatment failures. Therap Adv Fourteen-day high-dose esomeprazole, amoxicillin and met- Gastroenterol 2019;12:1756284819874922. ronidazole as third-line treatment for Helicobacter pylori 48. López-Góngora S, Puig I, Calvet X, et al. Systematic review infection. Int J Clin Pract 2017;71:e13004. and meta-analysis: susceptibility-guided versus empirical 35. Chen PY, Wu MS, Chen CY, et al. Systematic review with antibiotic treatment for Helicobacter pylori infection. J Anti- meta-analysis: the efficacy of levofloxacin triple therapy as microb Chemother 2015;70:2447-2455. the first- or second-line treatments of Helicobacter pylori 49. Chen Q, Long X, Ji Y, et al. Randomised controlled trial: sus- infection. Aliment Pharmacol Ther 2016;44:427-437. ceptibility-guided therapy versus empiric bismuth quadruple 36. Hsu PI, Wu DC, Chen A, et al. Quadruple rescue therapy therapy for first-line Helicobacter pylori treatment. Aliment for Helicobacter pylori infection after two treatment failures. Pharmacol Ther 2019;49:1385-1394. Eur J Clin Invest 2008;38:404-409. 50. Ong S, Kim SE, Kim JH, et al. Helicobacter pylori eradica- 37. Ciccaglione AF, Tavani R, Grossi L, Cellini L, Manzoli L, tion rates with concomitant and tailored therapy based on Marzio L. Rifabutin containing triple therapy and rifabutin 23S rRNA point mutation: a multicenter randomized con- with bismuth containing quadruple therapy for third-line trolled trial. Helicobacter 2019;24:e12654. treatment of Helicobacter pylori infection: two pilot studies. 51. Liou JM, Lee YC, Wu MS. Treatment of Helicobacter pylori Helicobacter 2016;21:375-381. infection and its long-term impacts on gut microbiota. J 38. Gasbarrini A, Ojetti V, Armuzzi A, et al. Efficacy of a mul- Gastroenterol Hepatol 2020;35:1107-1116. tistep strategy for Helicobacter pylori eradication. Aliment 52. Lee SK, Lee SW, Park JY, et al. Effectiveness and safety of Pharmacol Ther 2000;14:79-83. repeated quadruple therapy in Helicobacter pylori infec- 39. Vicente R, Sicilia B, Gallego S, Revillo MJ, Ducóns J, Gomol- tion after failure of second-line quadruple therapy: repeated lón F. Helicobacter pylori eradication in patients with peptic quadruple therapy as a third-line therapy. Helicobacter ulcer after two treatment failures: a prospective culture- 2011;16:410-414. guided study. Gastroenterol Hepatol 2002;25:438-442. 53. Murakami K, Furuta T, Ando T, et al. Multi-center random- 40. Cammarota G, Martino A, Pirozzi G, et al. High efficacy ized controlled study to establish the standard third-line of 1-week doxycycline- and amoxicillin-based quadruple regimen for Helicobacter pylori eradication in Japan. J Gas- regimen in a culture-guided, third-line treatment approach troenterol 2013;48:1128-1135. for Helicobacter pylori infection. Aliment Pharmacol Ther 54. Gisbert JP, Perez-Aisa A, Rodrigo L, et al. Third-line rescue 2004;19:789-795. therapy with bismuth-containing quadruple regimen after 41. Yahav J, Samra Z, Niv Y, et al. Susceptibility-guided vs. em- failure of two treatments (with clarithromycin and levofloxa- piric retreatment of Helicobacter pylori infection after treat- cin) for H. pylori infection. Dig Dis Sci 2014;59:383-389. ment failure. Dig Dis Sci 2006;51:2316-2321. 55. Rodríguez de Santiago E, Martín de Argila de Prados C, 42. Tay CY, Windsor HM, Thirriot F, et al. Helicobacter pylori Marcos Prieto HM, et al. Limited effectiveness with a 10-day eradication in Western Australia using novel quadruple ther- bismuth-containing quadruple therapy (Pylera®) in third- apy combinations. Aliment Pharmacol Ther 2012;36:1076- line recue treatment for Helicobacter pylori infection. A real- 1083. life multicenter study. Helicobacter 2017;22:e12423. 43. Fiorini G, Vakil N, Zullo A, et al. Culture-based selection 56. Lim JH, Kim SG, Song JH, et al. Efficacy of levofloxacin- therapy for patients who did not respond to previous treat- based third-line therapy for the eradication of Helicobacter

10 www.gutnliver.org Liou JM, et al: Treatment of Refractory Helicobacter pylori Infection

pylori in peptic ulcer disease. Gut Liver 2017;11:226-231. 63. Sugimoto M, Sahara S, Ichikawa H, Kagami T, Uotani T, Fu- 57. Okimoto K, Arai M, Saito K, et al. Efficacy of levofloxacin ruta T. High Helicobacter pylori cure rate with sitafloxacin- based triple and high-dose PPI-amoxicillin dual eradication based triple therapy. Aliment Pharmacol Ther 2015;42:477- therapy for Helicobacter pylori after failures of first- and 483. second-line therapies. Int Sch Res Notices 2014;2014:631501. 64. Furuta T, Sugimoto M, Kodaira C, et al. Sitafloxacin-based 58. Tursi A, Picchio M, Elisei W. Efficacy and tolerability of a third-line rescue regimens for Helicobacter pylori infection third-line, levofloxacin-based, 10-day sequential therapy in in Japan. J Gastroenterol Hepatol 2014;29:487-493. curing resistant Helicobacter pylori infection. J Gastrointes- 65. Matsuzaki J, Suzuki H, Nishizawa T, et al. Efficacy of tin Liver Dis 2012;21:133-138. sitafloxacin-based rescue therapy for Helicobacter pylori 59. Mori H, Suzuki H, Matsuzaki J, Masaoka T, Kanai T. 10-Year after failures of first- and second-line therapies. Antimicrob trends in Helicobacter pylori eradication rates by sitafloxa- Agents Chemother 2012;56:1643-1645. cin-based third-line rescue therapy. Digestion 2020;101:644- 66. Hirata Y, Ohmae T, Yanai A, et al. Sitafloxacin resistance 650. in Helicobacter pylori isolates and sitafloxacin-based triple 60. Saito Y, Konno K, Sato M, et al. Vonoprazan-based third-line therapy as a third-line regimen in Japan. Int J Antimicrob therapy has a higher eradication rate against sitafloxacin- Agents 2012;39:352-355. resistant Helicobacter pylori. Cancers (Basel) 2019;11:116. 67. Gisbert JP, Castro-Fernandez M, Perez-Aisa A, et al. Fourth- 61. Hirata Y, Serizawa T, Shichijo S, et al. Efficacy of triple line rescue therapy with rifabutin in patients with three therapy with esomeprazole, amoxicillin, and sitafloxacin as Helicobacter pylori eradication failures. Aliment Pharmacol a third-line Helicobacter pylori eradication regimen. Int J Ther 2012;35:941-947. Infect Dis 2016;51:66-69. 68. Mori H, Suzuki H, Matsuzaki J, et al. Rifabutin-based 10- 62. Mori H, Suzuki H, Matsuzaki J, et al. Efficacy of 10-day day and 14-day triple therapy as a third-line and fourth-line sitafloxacin-containing third-line rescue therapies for Heli- regimen for Helicobacter pylori eradication: a pilot study. cobacter pylori strains containing the gyrA mutation. Heli- United European Gastroenterol J 2016;4:380-387. cobacter 2016;21:286-294.

https://doi.org/10.5009/gnl20330 11